tbuckley/cabot-search huggingface dataset:
Abstract 4788: Oxidative stress promotes colorectal cancer aggressiveness through transmembrane chloride intracellular channel 1 (tmCLIC1) antioxidant activity
Authors: Francesca Cianci, Ivan Verduci, Carlotta Tacconi, Gaetano Cannavale, Matteo Ranucci, Giulia Bertolini, Paolo Malatesta, Federica Barbieri, Alessandro Fantin, Luca Roz, Tullio Florio, Michele Mazzanti
Journal: Cancer Research (2023)

Abstract In developed countries, colorectal cancer is the third leading cause of mortality. Despite significant advances in therapeutic approaches, metastases remain the primary concern in the treatment of colorectal cancer. Ion channels have an important role in the development of aggressive behavior, but the majority of them are involved in regular physiological activities. Chloride Intracellular Channel 1 (CLIC1) is a promising contender among the new possible biomarkers. CLIC1 is expressed as a cytosolic monomer by all cell types during physiological homeostasis. The main characteristic of this protein is that it can exist in both cytosolic and transmembrane forms (tmCLIC1), with the latter being involved in a variety of clinical conditions, including cancer. CLIC1 mRNA overexpression in colorectal cancer cells has been linked to a poor prognosis. The primary goal of this study is to understand the role of tmCLIC1 in the carcinogenesis, invasion, and migratory potential of colorectal cancer. We initially investigated the level of CLIC1 protein expression and the activity of its transmembrane form as an ion channel in numerous colorectal cancer cells at various stages of development. Our results show that tmCLIC1 protein expression and activity are related to cell aggressiveness, and that its role in cellular proliferation, migration, and invasion is critical. The role of tmCLIC1 activity in colorectal cancer was confirmed also in in vivo models. Experiments in zebrafish and mouse models have shown that silencing CLIC1 impairs primary tumor development and significantly reduces the generation of distal metastases. Furthermore, when the CLIC1 protein is missing, many distinct metastatic genes are downregulated, particularly those associated to oxidative stress, typical of cancer cells. As a matter of fact, CLIC1's peculiar activity and its interaction with glutathione make this protein critical for the redox equilibrium of colorectal cancer cells. Overall, the findings could be considered as a beginning point for elucidating a mechanism of action that could constitute a new milestone in anticancer research. Citation Format: Francesca Cianci, Ivan Verduci, Carlotta Tacconi, Gaetano Cannavale, Matteo Ranucci, Giulia Bertolini, Paolo Malatesta, Federica Barbieri, Alessandro Fantin, Luca Roz, Tullio Florio, Michele Mazzanti. Oxidative stress promotes colorectal cancer aggressiveness through transmembrane chloride intracellular channel 1 (tmCLIC1) antioxidant activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4788.
Abstract 5432: Validation of spatial gene expression patterns predicted by deep convolutional neural networks from breast cancer histopathology images
Authors: Kathy Ton, Yinxi Wang, Liuliu Pan, Kimmo Kartasalo, Balazs Acs, Philippe Weitz, Liang Zhang, Yan Liang, Johan Hartman, Masi Volkonen, Christer Larsson, Pekka Ruusuvuori, Joseph Beechem, Mattias Rantalainen
Journal: Cancer Research (2023)

Abstract Molecular profiling is central in cancer precision medicine but remains costly and is only based on tumor average profiles. Morphologic patterns observable in histopathology sections from tumors are determined by the underlying molecular phenotype and therefore have the potential to be exploited for the prediction of molecular phenotypes. Transcriptome-wide expression morphology (EMO) analysis with deep convolutional neural networks (CNN) enables the prediction of mRNA expression and proliferation markers from routine histopathology whole slide images in breast cancer. The NanoString GeoMx® Digital Spatial Profiler (DSP) platform has capabilities of associating crucial spatial information with intratumor variabilities of gene expression, serving as an ideal tool to characterize and validate the prediction of intratumor heterogeneity. The GeoMx platform also provides functionalities of overlaying and aligning hematoxylin and eosin (H&amp;E) whole slide scans on serial tissue sections with morphology marker staining to facilitate region of interest (ROI) selection to match relevant image tiles from the model input, which is a key step to ensure accuracy for the evaluation of the model predictions. The GeoMx RNA Immune Pathways Panel contains 84 gene targets including key genes involved in immune pathways and tumorigenesis and was used to validate the prediction of mRNA expression output from deep CNN models. Citation Format: Kathy Ton, Yinxi Wang, Liuliu Pan, Kimmo Kartasalo, Balazs Acs, Philippe Weitz, Liang Zhang, Yan Liang, Johan Hartman, Masi Volkonen, Christer Larsson, Pekka Ruusuvuori, Joseph Beechem, Mattias Rantalainen. Validation of spatial gene expression patterns predicted by deep convolutional neural networks from breast cancer histopathology images. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5432.
Abstract 6158: BGB-24714, a novel oral IAP antagonist, displayed significant anti-tumor activities in preclinical models as a monotherapy and in combination with paclitaxel
Authors: Jie Li, Nan Hu, Yilu Zhang, Xiaolong Yang, Minjuan Deng, Wenfeng Gong, Longbo Yin, Yong Liu, Yajuan Gao, Wei Wei, Xing Wang, Xinyi Liang, Yanwen Ma, Xuxing Sang, Chang Liu, Jingyuan Wang, Qianqian Lu, Fengtao Song, Xi Yuan, Yibing Wang, Jing Li, Wei Jin, Xuesong Liu, Xiaomin Song
Journal: Cancer Research (2023)

Abstract Background: Evasion of apoptosis is identified as one of the essential hallmarks of cancer and upregulation of inhibitor of apoptosis proteins (IAPs) is one of the mechanisms by which tumor cells evade apoptosis. An oral SMAC mimetic and antagonist of cellular IAP1 (cIAP1) and X-linked IAP (XIAP), BGB-24714, is currently investigated in a phase 1a/1b oncology trial in patients with advanced or metastatic solid tumors (NCT05381909). Here, we evaluated the anti-tumor activity of BGB-24714 as a single agent or in combination with paclitaxel in preclinical models. Results: BGB-24714 effectively inhibited cIAP1 by inducing its degradation in MDA-MB-231 cells, with an EC50 of 2.5 nM. BGB-24714 also potently antagonized the inhibitory interaction of XIAP with caspase-9 and induced caspase-9 autoactivation in MDA-MB-231 cells, with an EC50 of 23 nM. In a total of 25 breast cancer cell lines treated with TNFα, BGB-24714 potently inhibited the in vitro proliferation of 5 breast cancer cells with EC50 &amp;lt; 100 nM. In pharmacodynamics studies, single dose administration of BGB-24714 significantly induced degradation of cIAP1 and antagonism of the XIAP: Smac interaction in the MDA-MB-231 xenograft model in a dose dependent manner. Using the same model, BGB-24714 exhibited dose-dependent anti-tumor activities as a single agent. The tumor growth inhibition rates were 30%, 52% and 73% in low to high dosage treatment groups. Furthermore, BGB-24714 at medium dosage level demonstrated synergized anti-tumor activity in HCC1806 xenograft model when used in combination with paclitaxel. In intermittent dosing study, BGB-24714 with the intermittent dosing schedule demonstrated significant but slightly less effective anti-tumor activity than the continuous dosing schedule. In summary, BGB-24714, as a novel oral IAP antagonist, showing significant anti-tumor activities in preclinical models, which is promising and warrants the testing of the compound in human. Citation Format: Jie Li, Nan Hu, Yilu Zhang, Xiaolong Yang, Minjuan Deng, Wenfeng Gong, Longbo Yin, Yong Liu, Yajuan Gao, Wei Wei, Xing Wang, Xinyi Liang, Yanwen Ma, Xuxing Sang, Chang Liu, Jingyuan Wang, Qianqian Lu, Fengtao Song, Xi Yuan, Yibing Wang, Jing Li, Wei Jin, Xuesong Liu, Xiaomin Song. BGB-24714, a novel oral IAP antagonist, displayed significant anti-tumor activities in preclinical models as a monotherapy and in combination with paclitaxel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6158.
Abstract 5437: Vision transformers for breast cancer human epidermal growth factor receptor 2 (HER2) expression staging without immunohistochemical (IHC) staining
Authors: Gelan Ayana, Eonjin Lee, Se-woon Choe
Journal: Cancer Research (2023)

Abstract Purpose: Staging of human epidermal growth factor receptor 2 (HER2) expression is crucial for evaluating the effectiveness of breast cancer treatment. However, it involves an expensive and challenging immunohistochemical (IHC) staining in addition to hematoxylin and eosin (H&amp;E) staining. Here, we argue that customized vision transformers are effective in breast cancer HER2 expression staging using only H&amp;E-stained images. Methods: Our algorithm has three modules: a localization module to weakly localize the necessary features of an image via spatial transformers, an attention module to learn global features from the image using vision transformers, and a loss module that determines the closest one to a HER2 expression level from input images by calculating the ordinal loss. We utilized a publicly available breast cancer HER2 expression dataset, the breast cancer immunohistochemical image (BCI) dataset, which contains paired H&amp;E and IHC stained images. Results were calculated with 95% confidence intervals and t-test was used to evaluate the significance of the proposed model against other models. Results: Our approach achieved area under receiver operating characteristics curve (AUC), precision, sensitivity, and specificity of 0.9202±0.01, 0.922±0.01, 0.876±0.01, and 0.959±0.02, respectively, averaged over five-fold cross-validation, in staging HER2 expression. The proposed method showed better performance than the conventional vision transformer model and state-of-the-art convolutional neural network models with statistical significance of p&amp;lt;0.01 in all cases. Conclusion: Our findings are important in assisting HER2 expression staging in breast cancer treatment, while avoiding the need for an expensive and time-consuming IHC staining procedure. Comparison of the proposed model with state-of-the-art models. CNN-convolutional neural network Study Neural network Model AUC Couture et al. (2018) CNN VGG16 0.75 Shamai et al. (2019) CNN ResNet50 0.74 Yang et al. (2021) CNN ResNet50 0.76 Naik et al. (2020) CNN ResNet50 0.78 Khater et al. (2021) CNN ShuffleNet 0.75 Conde-Sousa et al. (2022) CNN EfficientNet 0.88 Farahmand et al. (2022) CNN InceptionV3 0.90 Proposed Vision transformer vitb_16 0.92 Citation Format: Gelan Ayana, Eonjin Lee, Se-woon Choe. Vision transformers for breast cancer human epidermal growth factor receptor 2 (HER2) expression staging without immunohistochemical (IHC) staining. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5437.
Abstract 6160: Targeting RNA N6-methyladenosine methyltransferase, METTL3 activates p53 and apoptosis pathways in osteosarcoma cells
Authors: Seungjae Shin, Yumi Oh, Yoojin Yang, Sung-Yup Cho
Journal: Cancer Research (2023)

Abstract Osteosarcoma (OS) is a malignant tumor which is mesenchymal origin from bone stroma. The 5-year overall survival of localized OS is approximately 70%, however patients who have metastasis to other organs, mostly lung, have a poor 5-year survival rate, approximately 20%. Recently, oncogenic role of Methyltransferase-like 3 (METTL3), which is the only catalytic subunit of RNA N6-Methyladenosine methyltransferase complex, has been suggested, but its mechanism in OS is still unclear. To elucidate the roles of METTL3 in OS, we generated METTL3 knock-out U2OS osteosarcoma cell lines by CRISPR knock-out system. Knock-out of METTL3 decreased cell proliferation on U2OS cells, which was assessed by WST-1 assay and manual cell counting assay. Also, RNA-sequencing was conducted in METTL3 wild type and knock-out cell lines. Gene set enrichment analysis (GSEA) revealed that gene sets of ‘Programmed cell death’ in gene ontology (GO) category, ‘p53 pathway’ and ‘Apoptosis’ in HALLMARK gene sets, and ‘p53 signaling pathway’ and ‘Apoptosis’ in KEGG pathway were enriched in METTL3 knock-out cells. To validate the result of GSEA in our METTL3 knock-out cells, mRNA and protein levels of GADD45A and CDKN1A, which are downstream targets of p53, and BAX and BAK, which are apoptosis-related molecules induced by p53, were detected by real-time PCR and western blot, respectively, and these genes were upregulated in METTL3 knock out cell lines. Collectively, these results suggest that inhibition of METTL3 is potential therapeutic targets against OS by activating p53 and apoptosis pathways. Citation Format: Seungjae Shin, Yumi Oh, Yoojin Yang, Sung-Yup Cho. Targeting RNA N6-methyladenosine methyltransferase, METTL3 activates p53 and apoptosis pathways in osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6160.
Abstract 1547: The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies
Authors: Pernille Barkholt, Agnieszka Wozniak, Chao-Chi Wang, Che-Jui Lee, Lore De Kock, Lars H. Engelholm, Carmel Lynch, Dominik Mumberg, Patrick Schöffski
Journal: Cancer Research (2023)

Abstract Background: Soft tissue sarcoma (STS) is a complex family of rare malignancies with high unmet medical need. uPARAP is an endocytic receptor expressed at low levels on selected mesenchymal cell types, which internalizes fragments of collagen and transfers them to the lysosome for degradation. Besides its physiological role, uPARAP is considered a critical modulator of the tumor microenvironment. Here, for the first time, we explored the molecular epidemiology of uPARAP in sarcoma tissue to validate this receptor as target for the development of ADCs in this indication. Methods: uPARAP expression was assessed in STS-specific tissue microarrays by immunohistochemistry in tissue samples from more than three hundred individual donors. Stainings were assessed by histopathologic scoring and grouped into high, medium and low expressing subgroups. Results: uPARAP was found to be strongly over-expressed in a high percentage of cases of common STS, with variations in terms of incidence and level of expression between histological subtypes. High uPARAP expression was found in fibro- (86% of cases), synovial (84%), dedifferentiated lipo- (68%), pleomorphic lipo- (65%), myxofibro- (59%), leiomyo- (49%), and myxoid liposarcoma (24%). Work is ongoing in additional sarcoma subtypes. Conclusions: Based on protein expression uPARAP is an attractive emerging therapeutic target for the development of uPARAP-binding ADCs in a broad range of mesenchymal malignancies. In addition, expression of uPARAP in STS may serve as a potential marker for patient selection in early clinical studies with uPARAP-targeting ADCs. Citation Format: Pernille Barkholt, Agnieszka Wozniak, Chao-Chi Wang, Che-Jui Lee, Lore De Kock, Lars H. Engelholm, Carmel Lynch, Dominik Mumberg, Patrick Schöffski. The urokinase plasminogen activator receptor-associated protein (uPARAP) is an attractive target for the development of antibody-drug conjugates (ADCs) for treatment of mesenchymal malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1547.
Abstract 1748: Mcl-1 inhibitor KS18 overcomes bortezomib, venetoclax, and ABT-737 resistance in multiple myeloma
Authors: Omar S. Al Odat, Krishne Gowda, Shantu G. Amin, Tulin Budak- Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey
Journal: Cancer Research (2023)

Abstract Recent advancements in multiple myeloma (MM) therapy have not changed the fact that it is incurable, and all patients experience relapse or become refractory. Thus, more effective treatments are needed to prolong the survival of MM patients. Anti-apoptotic myeloid cell leukemia 1 (Mcl-1) overexpression is correlated with poor prognosis and drug resistance in MM. Nonetheless, there is a lack of effective Mcl-1 inhibitors. To address this unmet clinical need, we developed KS18, a Mcl-1 inhibitor. We generated respective resistant cells to investigate whether KS18 may overcome acquired resistance against various available drugs in the clinic including bortezomib, venetoclax, and ABT-737. KS18 was effective against all MM cells with IC50 values ranging between 1.5 to 2.5µM. KS18 showed significant Mcl-1 inhibition in various MM cells including resistant cells. Importantly, KS18 re-sensitizes resistant cells to bortezomib and other chemotherapeutic drugs. Moreover, KS18 was able to enhance the anti-myeloma activity of venetoclax and ABT-737 treatments toward bortezomib-resistant cells. These results indicate that KS18 possesses the potential to overcome resistance by targeting Mcl-1. Our future studies in patient samples and in vivo model are proposed for further preclinical assessment of this exciting molecule. Citation Format: Omar S. Al Odat, Krishne Gowda, Shantu G. Amin, Tulin Budak- Alpdogan, Subash C. Jonnalagadda, Manoj K. Pandey. Mcl-1 inhibitor KS18 overcomes bortezomib, venetoclax, and ABT-737 resistance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1748.
Abstract 4644: Modeling the effects of niche specific microenvironmental changes on patient-derived organoids
Authors: Jennifer von Schlichting, Stefan Peidli, Markus Morkel, Nils Blüthgen, Leona Simon
Journal: Cancer Research (2023)

Abstract Here, we present an approach to study the effects of microenvironmental changes on inter- and intratumoral heterogeneity using colorectal cancer (CRC) patient-derived organoids. We identified relevant paracrine interactions between stromal and tumor cells based on the expression of ligand-receptor pairs in single cell-RNAseq data of 12 colorectal cancer patients. Physiological relevance was tested by adding CRC stroma-derived ligands to patient-derived organoids. A systematic screening of different conditions was enabled by multiplexed mass cytometry and scRNAseq analysis. We also aimed to model the effects of a changing extracellular matrix composition, by supplementing the laminin/collagen IV rich environment with other known ECM proteins such as collagen I to identify the impact of a changing substrate on cell plasticity. We found that ECM parameters as well as niche specific paracrine factors affect proliferation, differentiation, and developmental trajectories of colorectal cancer patient-derived organoids. We hypothesize that supplementing patient-derived organoids in vitro with physiologically relevant factors and substrates may expand the phenotypic space in which organoid cells differentiate, resulting in a more versatile preclinical model system.Our data provide insights into non-genetic sources of inter- and intratumoral heterogeneity resulting in differential drug responses. Additionally, they can serve as guidelines to improve existing patient-derived colorectal cancer models and provide a feasible approach to address common limitations in organoid culture. Citation Format: Jennifer von Schlichting, Stefan Peidli, Markus Morkel, Nils Blüthgen, Leona Simon. Modeling the effects of niche specific microenvironmental changes on patient-derived organoids. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4644.
Abstract 5014: HPK1 gene knockout reporter cell line: an efficient drug screening system
Authors: Yunpeng Zhai, Lidan Li, Jianyu Hao, Yuqing Hu, Jinying Ning, Feng Hao
Journal: Cancer Research (2023)

Abstract Immunotherapy is the stimulation of the immune system, improving on the ability of immune system to treat cancer. It is expected to be the most effective therapy for patients with tumor metastasis. Checkpoint inhibitor (CPI) therapy is a form of cancer immunotherapy which can block inhibitory checkpoints, restoring immune system function. Tumor cells could recruit immunomodulatory cells and induce inhibitory signals, resulting in losing immunomodulatory. Therefore, there is an urgent need to develop new therapeutic agents that work in concert with CPI. HPK1, also known as MAP4K1, can act as a negative regulator of activation signals generated by T cell receptor (TCR). The development and screening of HPK1 inhibitors have great potential in the cancer immunotherapy. Herein, we constructed a HPK1 knockout reporter cell line Jurkat-NFAT-Luc2-HPK1-Knockout-Cell-Line by CRISPR/Cas9 which can be used in high-throughput HPK1 inhibitors screening. Wild type cells were incubated with HPK1 inhibitors and luciferase signals were compared in HPK1-knockout cells. Our HPK1 knockout reporter cell line has high sensitivity and specificity. The reporter system can achieve high-throughput compound library screening. After selected the compound with selective inhibitory activity, further validation and optimization would be performed. Moreover, we constructed a Jurkat-HPK1-HiBiT reporter cell line by CRISPR/Cas9. It can be used in the screening of HPK1 degradants. We believe that HPK1 gene editing cell lines play an important role in the high-throughput screening of drugs. It could facilitate the development of drugs in tumor immunotherapy. Citation Format: Yunpeng Zhai, Lidan Li, Jianyu Hao, Yuqing Hu, Jinying Ning, Feng Hao. HPK1 gene knockout reporter cell line: an efficient drug screening system. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5014.